the apolipoprotein c-iii story: epidemiology, metabolism ... · the apolipoprotein c-iii story:...
TRANSCRIPT
![Page 1: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/1.jpg)
The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic
science lead to treatmentFrank Sacks, M.D.
Professor of Cardiovascular Disease Prevention, Nutrition Department,
Harvard Chan School of Public HealthProfessor, Department of Medicine,
Harvard Medical School and Brigham & Women’s Hospital
![Page 2: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/2.jpg)
Disclosures
• Inventor on patent to Harvard U. on methods to measure and use apoC3.
• Consultant: Lilly, Amgen, ISIS, Pfizer
![Page 3: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/3.jpg)
Cholesteryl esterTriglyceride
Apo B
Apo C-I
Apo C-IIApo C-IIIApo E
ApoB LipoproteinsHave Many Small Apolipoproteins
Apo A-V
Small apolipoproteins modulate the metabolism of Chylomicrons, VLDL and LDL
Apo A-II
LpLChylomicrons, VLDL and LDL
![Page 4: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/4.jpg)
Apolipoprotein CIII and E
Present on some VLDL, LDL, and HDL particles
LDL
LDL without apoCIII
LDL apoCIIIapoCIII
LDLwith apoCIII
LDL apoEapoCIII
LDLwith apoCIII and apoE
![Page 5: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/5.jpg)
ApoC-III in SDS Micelles:79 amino acids; 6 amphipathic helices with semi-flexible hinges, negative polar faces
Gangabadage..Wijmenga. JBC 2008;283:17456
Similarity to LDL receptor binding lysine motifs of apoE, apoB, and RAP.
Causes binding of VLDL and LDL to proteoglycans (Chait; Boren)
![Page 6: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/6.jpg)
Apolipoprotein C-III: Associated with CHD
• Apo CIII in apoB lipoproteins (LpB:CIII) associated with progression of coronary atherosclerosis (Blankenhorn, Alaupovic et al. 1990; Hodis 1994)
• “LpB:CIII” strongest lipoprotein association with progression of coronary atherosclerosis in statin-treated patients, LDL=82 mg/dl (Alaupovic 1997)
• Apo CIII in apoB LP associated with CHD in case-control studies (Chivot..Fruchart 1990; Luc..1996).
• Do prospective studies confirm high risk of apoCIII?
![Page 7: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/7.jpg)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Q1 Q2 Q3 Q4 Q5
CARE
Triglycerides, VLDL-Apo B and Apo CIII in VLDL and LDL:
Risk Factors for Coronary Events
VLDL Apo B
Apo CIII in VLDL+ LDL
Triglycerides
p=0.04
p=0.04
Univariate Multivariate
RR
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Q1 Q2 Q3 Q4 Q5
Triglycerides
p=0.03
RR
Sacks, Alaupovic, et al. Circulation 2000;102:1886-1892
N=418 cases of MI or CHD Death
![Page 8: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/8.jpg)
N=121 with CVD event
LDL particles with apoCIII:Risk of Recurrent Cardiovascular
Events in Diabetes: CARE trial
Lee SJ, Campos H, Moye L, Sacks FM. Arterioscler Thromb Vasc Biol. 2003;23:853.
* without apoCIII, RR=2.2, P=0.07** with apoCIII, RR=6.6, P < .0001
Quartiles: apoB concentrations 0
1
2
3
4
5
6
1 2 3 4LDL particle concentration (Quartiles of apoB)
1.0
6.6**
1.7
3.0
1.0 1.01.6
2.2*
![Page 9: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/9.jpg)
Apolipoprotein B in LDL without apolipoprotein C-III, P for trend=0.81Apolipoprotein B in LDL with apolipoprotein C-III, P for trend<0.001
Quintile
1 2 3 4 5
Rel
ativ
e ris
k of
co
rona
ry h
eart
dis
ease
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
AFirst coronary event in US Men and WomenLDL with apoC‐III and LDL without apoC‐III:
749 cases of first MI or coronary death
Mendivil, Rimm, Furtado, Sacks. Circulation 2011
![Page 10: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/10.jpg)
LDL subpopulations according to contents of apoE and apoC III
Mendivil CO et al. J Am Heart Assoc 2013;2:e000130
![Page 11: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/11.jpg)
Mendivil C O et al. J Am Heart Assoc 2013;2:e000130
ApoE on VLDL and LDL Lessens the Risk Associated with ApoC-III
![Page 12: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/12.jpg)
ApoC-III:Mechanistic Studies in Humans
Can we connect the findings on CHD risk to metabolic diversity of
the lipoprotein types?
![Page 13: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/13.jpg)
TG and cholesterolexport
Cholesterol export
VLDL: without apoEwith apoCIII
CIII
VLDL: with apoEwith apoCIII
CIII
apoE
+‐
IDL: with apoEwith apoCIII
‐ ‐‐ +
+
* *
The Liver Secretes All Sizes of ApoB Lipoproteins, and Subspecies with ApoC-III and ApoE
Sacks FM. Curr Opinion Lipidol 2015
![Page 14: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/14.jpg)
Va11 mg
Vb24 mg
IDL110 mg
LDL3906 mg
LDL2305 mg
LDL1185 mg
E- C3-
Va32 mg
Vb34 mg
IDL50 mg
LDL336 mg
LDL238 mg
LDL144 mgE- C3+
Va3 mg
Vb3 mg
IDL14 mgE+ C3-
Va24 mg
Vb27 mg
IDL15 mg
LDL33 mg
LDL25 mg
LDL19 mgE+ C3+
79%
21%
91%
9%
13% 7%
4%
15%
87% 93%
27%
59% 47% 29% 36% 39%
44% 40% 17% 19% 25%
46% 48% 46%63% 63% 100%
20% 13% 34% 8% 12%9%
91%
Complexity of VLDL and LDL Metabolism in Plasma
ApoB Secretion(11 mg·kg-1·day-1)
30%Lipolysis
Lipolysis,Conversion
To E-C3-
Clearance,Lipolysis
Clearance
Zheng C,, Sacks F. JLR 2007;48:1190
![Page 15: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/15.jpg)
Apolipoprotein C-III and E: A High Carbohydrate Diet and Hypertriglyceridemia
Impair VLDL MetabolismVLDL E-CIII+ Dense LDL
VLDL E+CIII+
TG TG
Zheng C,, Sacks F. J Lipid Res 2007;48:1190; Am J Clin Nutr 2008;88:272
++ ++
-
-
-
Small VLDL, IDLClearance
+
![Page 16: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/16.jpg)
Normal TGIntegral Involvement of ApoE in Normal
TG-Rich Lipoprotein Metabolism:High secretion of light and medium size LDL E-CIII-, fast clearance of dense LDL.
Low secretion of VLDL containing just apoC-III
High secretion of VLDL containing apoE and apoC-III; Clearance of apoE rich VLDL before it forms LDL.
Zheng C…Sacks FM. Circulation 2010.
E-CIII-
E-CIII+
E+CIII+
![Page 17: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/17.jpg)
Hypertriglyceridemia or High Carb DietIntegral Involvement of ApoC-III in Establishing
the Dense LDL Phenotype
Zheng C…Sacks FM. Circulation 2010; Am J Clin Nutr 2008;88:272.
High secretion of VLDL containing just apoC-III. Most converted to dense LDL. Slow clearance of dense LDL.
Low secretion of VLDL containing apoE and apoC-III
E-CIII-
E-CIII+
E+CIII+
![Page 18: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/18.jpg)
Why Hypothesize That ApoC-III Has Direct Effects on Vascular Cells?
ApoC-III containing VLDL and LDL have an outsized relation to CVD
compared with its low plasma concentration
![Page 19: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/19.jpg)
Monocytes, Macrophages
β1integrin
VLDL, LDL high apoCIII
Endothelial cellsligands (VCAM-1)
Kawakami A, Circulation 2006;113:691; 114:681; ATVB 2007;27:219
NFkB
TNFα, IL1β
Atherogenicity of apoC-III
TLR2
LOX-1
NFkB
![Page 20: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/20.jpg)
ApoCIII-induces VCAM-1 accumulation in vivo: reduction by pitavastatin
Ctrl ApoCIII ApoCIII +Pitavastatin
More VCAM-1Few VCAM-1 Less VCAM-1
0%
5%
10%
15%
1 2 3
VCAM
-1 P
ositi
ve A
rea
vs. t
otal
EC
Area
ApoCIII Pitavastatin+ ApoCIII
Ctrl
P=0.018 P=0.046
N=5 each
L LL
Zheng C…Aikawa M. Eur Heart J 2013
![Page 21: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/21.jpg)
HDL with ApoC-III: A Subspecies With an Adverse
Relation to CHD and Metabolism
![Page 22: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/22.jpg)
HDL Particles with ApoCIII Do Not Inhibit Monocytic Cell Adhesion to
Endothelial Cells
(μg chol/mL)
THP
-1 c
ell a
dhes
ion
(%)
*P<0.05
*
Circulation 2006;113:691
![Page 23: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/23.jpg)
Apolipoprotein C-III in HDL:Recurrent Coronary Events (CARE trial)
• ApoC-III concentration in HDL– Relative risk = 1.3 (0.8,2.0) for 5th vs 1st quintile, 8
vs 3 mg/dL• ApoC-III to apoA-I ratio in HDL
– Relative risk = 1.6 (1.0,2.5), p=0.05, for 0.4 vs 0.15 mol/mol
Sacks FM, Alaupovic P et al. Circulation 2000;102:1886
![Page 24: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/24.jpg)
HDL with Apo CIII is Associated with Coronary Heart Disease in Turkey
Onat …Assmann et al. Athero 2003;168:81
Men Women
OR
for C
HD
HDL apo C-III mg/dl
P<.05 P<.10
![Page 25: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/25.jpg)
Nurses and Other Health Professionals:Risk of First MI for HDL-C with and without apoCIII:
714 with First MI or Coronary Death
Quintiles of HDL-C
IRR
CH
D
0.3
0.5
1.0
2.0
3.0
HDL-C with CIIIP trend = 0.0005
HDL-C without CIIIP trend = 0.0001
Jensen M, Rimm E, Furtado J, Sacks FM. J Am Heart Assoc 2012.
![Page 26: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/26.jpg)
Clin Chem Acta 2010
ApoC-III in HDL Is a Component of a Proteomic Signature for CVD
![Page 27: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/27.jpg)
Obese Have Significantly More HDL with apoC‐III and apoE; and less HDL without apoC‐III or apoE
Normal Weight Group Obese Group
A E‐CIII‐
B
C
D
E+CIII‐
E‐CIII+
E+CIII+
Talayero B, Sacks F. J Lipid Res 2014
![Page 28: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/28.jpg)
ApoC3 Null Mutation Protects Against Coronary Atherosclerosis:
Carriers vs noncarriers
Pollin et al. Science 2008;322:1702
ApoC-III 50% of control
TG: 31 vs 57 mg/dl*
LDL-C: 116 vs 140 mg/dl*
HDL-C: 67 vs 55* mg/dl*
Coronary Ca+ 34% vs 54%*
![Page 29: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/29.jpg)
ApoC3 Variants Associated with Reduced TG Levels
Jorgensen et al. NEJM 2014
![Page 30: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/30.jpg)
ApoC3 Variants Associated with Reduced Incidence of Vascular Disease
Jorgensen et al. NEJM 2014
![Page 31: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/31.jpg)
ApoC3 Variants Associated with Reduced Incidence of Vascular Disease
Kathiresan et al. NEJM 2014
![Page 32: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/32.jpg)
Treatments That Reduce ApoCIII Containing Lipoproteins
• Fibrates (25-35%) [Ooi, Alaupovic et al. ATVB1997]• Statins (15-25%) [Dallinga-Thie et al. Diab Care
2004; Lamendola..Reaven et al Am J Cardiol 2005; Sacks et al Am J Cardiol 2002]
• Testosterone in postmenopausal women (62% for apoCIII in VLDL, 35% for apoCIII in LDL) [Chiuve..Sacks. J Clin Endocrinol Metab 2004)]
• Reduced carbohydrate diets, especially diets enriched in protein or unsaturated fat [Furtado..Sacks et al. AJCN2008]
• Weight loss with a range of macronutrient contents• Mipomersen, an apoB antisense oligonucleotide
(Furtado J..Sacks FM. J Lipid Res 2012)• Anti-apoC-III antisense oligonucleotide (ISIS)
![Page 33: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/33.jpg)
ISIS-ApoC3Rx Lowers apoC3 and TG in Healthy Participants
Graham M, Circ Res 2013
![Page 34: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/34.jpg)
ISIS-ApoC3Rx Lowers apoC3 and TG in Familial Chylomicronemia: LpL Deficiency
Gaudet D et al,N Engl J Med 2014
![Page 35: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/35.jpg)
ApoC-III: Putting It Together• Total and apoB lipoprotein apoC-III predicts CHD.• Even more, apoB concentration of LDL with apoC-
III is especially strong, independent predictor.• Adverse effects of apoC-III on apoB metabolism
and vascular cells, and Mendelian randomization studies provide a strong case for causality.
• ApoA-I concentration of HDL with apoC-III predicts increased CHD. Possible dysfunctional subspecies.
• Treatment to reduce apoC3 has potential to reduce CHD, especially in hyperTG
![Page 36: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/36.jpg)
![Page 37: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/37.jpg)
Light VLDLE+CIII+
Dense VLDL
E+CIII+
IDLE+CIII+ Light LDL
E+CIII+Medium LDL
E+CIII+Dense LDL
E+CIII+
Light VLDLE+CIII-
Light VLDLE-CIII+
Light VLDLE-CIII-
Dense VLDLE-CIII-
IDLE-CIII-
Light LDLE-CIII-
Med. LDLE-CIII-
Dense LDLE-CIII-
Dense VLDLE-CIII+
IDLE-CIII+ Light LDL
E-CIII+Medium LDL
E-CIII+Dense LDL
E-CIII+
Dense VLDLE+CIII-
IDLE+CIII-
Out46%
45%
Out47%
41%
Out46%
18%
Out62%
19%
Out58%
26%
Out100%
Out87%
13%
Out92%
8%
Out100%
Out15%
61%
Out20%
59%
Out35%
29%
Out8%
38%
Out13%
40%
Out8%
‐CIII 92%
Out22%
78%
Out8%
92%
Out3%
97%
Out100%
Out31%
69%
Out31%
69%
‐
‐
‐
+ +
+
+ ++
+
+
+
Metabolic Diversity of VLDL, IDL and LDL Subspecies: Sacks 2015
E+C+
E+C-
E-C+
E-C-
![Page 38: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/38.jpg)
ISIS-APOCIIIRx Treatment Significantly Reduced ApoC-III
38
Mean % Change in Fasting ApoC-III
R. Crooke, ISIS Pharmaceuticals, Presented at AHA ATVB Sessions,
May 1, 2014
![Page 39: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/39.jpg)
ISIS-APOCIIIRx Treatment Significantly Reduced Triglycerides
Mean % Change in Fasting Triglycerides
39
R. Crooke, ISIS Pharmaceuticals, Presented at AHA ATVB Sessions, May 1, 2014
![Page 40: The Apolipoprotein C-III Story: Epidemiology, metabolism ... · The Apolipoprotein C-III Story: Epidemiology, metabolism, and basic science lead to treatment Frank Sacks, M.D. Professor](https://reader030.vdocuments.net/reader030/viewer/2022013000/5bdee9d709d3f29b5f8b7340/html5/thumbnails/40.jpg)
ApoC-III Researchers
Carlos Mendivil, MD, ScD Chunyu Zheng, ScD
Majken Jensen, PhDBeatriz Talayero, M.D.